Myelodysplastic syndrome treatment
January 15 2016 by
Ray Sahelian, M.D.

Treatment of patients with a myelodysplastic syndrome (MDS) is challenging. The dilemma that confronts the management of myelodysplastic syndrome is illustrated by the availability of two drugs (5-azacitidine and decitabine) with an indication for all subtypes of this disease and another one (lenalidomide) for the management of a specific myelodysplastic syndrome subgroup, the 5q- syndrome. Current classifications and prognostic systems do not take into account the considerable clinical heterogeneity of myelodysplastic syndrome or their diverse biology. Supportive care, low-intensity treatment, acute myeloid leukemia-type therapy, and stem cell transplantation produce unsatisfactory results because patients continue to be exposed to the inherent complications of worsening cytopenias and leukemic transformation. Recent years have witnessed an evolution in our understanding of pathophysiology pathways in myelodysplastic syndrome. At the same time, many novel and targeted therapies are being investigated in clinical trials, offering patients the prospect of sustained benefit and changing the natural course of the disease. Hypomethylating agents, immunomodulatory drugs, and farnesyl-tranferase inhibitors have produced very promising results in terms of response and survival in myelodysplastic syndrome patients.

Cancer Immunol Immunother. 2015. Maitake mushroom extract in myelodysplastic syndromes (MDS): a phase II study. Myelodysplastic syndromes (MDS) are characterized by ineffective erythropoiesis with dysplastic bone marrow leading to peripheral cytopenia, risk of infection, and progression to acute myelogenous leukemia. Maitake mushroom beta-glucan, a dietary supplement, stimulates hematopoietic progenitor cell differentiation, granulocyte colony-stimulating factor production, and recovery of peripheral blood leukocytes after bone marrow injury. This phase II trial examined the effects of Maitake on innate immune function in MDS. Myelodysplastic syndromes patients with International Prognostic Scoring System Low- and Intermediate-1-risk disease received oral Maitake extract at 3 mg/kg twice daily for 12 weeks. Primary endpoints included neutrophil count and function tested as endogenous or stimulated neutrophil production of reactive oxygen species (ROS) by flow cytometry compared with age-matched healthy controls (HC). ROS activators were Escherichia coli, phorbol ester, and the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Complete blood counts, chemistry panels, iron studies, and monocyte function were evaluated. Of 21 patients enrolled, 18 completed the study and were evaluable. Maitake increased endogenous (basal) neutrophil and monocyte function. Pre-treatment monocyte response to E. coli was reduced in MDS patients compared with HC and increased after treatment. fMLP-stimulated ROS production response also increased. Asymptomatic eosinophilia occurred in 4 patients. Other changes in albumin, hemoglobin, and total protein were not clinically relevant. Maitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment demonstrate that Maitake has beneficial immunomodulatory potential in MDS.

Myelodysplastic syndrome and decitabine
Dacogen (decitabine, MGI Pharma) for Injection is available for the treatment of patients with MDS, including previously treated and untreated, de novo, and secondary myelodysplastic syndrome of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia), and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Occup Environ Med. 2014. Risk of myeloproliferative disease and chronic myeloid leukaemia following exposure to low-level benzene in a nested case-control study of petroleum workers. Benzene exposure has been associated with increased risk of leukaemia and myelodysplastic syndrome. Existing studies are sparse for other lymphohaematopoietic cancer subtypes, such as myeloproliferative disease (MPD) and the related chronic myeloid leukaemia (CML).  No convincing association was identified between MPD or CML and low exposure to benzene. The greater risk for exposures experienced in the 20 years before diagnosis needs investigating in more powerful studies with a wider range of exposure to benzene, and the biological plausibility further examined from a mechanistic viewpoint.

Oncotarget. 2015. Identification and validation of the dopamine agonist bromocriptine as a novel therapy for high-risk myelodysplastic syndromes and secondary acute myeloid leukemia. Myelodysplastic syndromes (MDS) represent a broad spectrum of diseases characterized by their clinical manifestation as one or more cytopenias, or a reduction in circulating blood cells. MDS is predominantly a disease of the elderly, with a median age in the UK of around 75. Approximately one third of MDS patients will develop secondary acute myeloid leukemia (sAML) that has a very poor prognosis. Unfortunately, most standard cytotoxic agents are often too toxic for older patients. This means there is a pressing unmet need for novel therapies that have fewer side effects to assist this vulnerable group. This challenge was tackled using bioinformatic analysis of available transcriptomic data to establish a gene-based signature of the development and progression of MDS. This signature was then used to identify novel therapeutic compounds via statistically-significant connectivity mapping. This approach suggested re-purposing an existing and widely-prescribed drug, bromocriptine as a novel potential therapy in these disease settings. This drug has shown selectivity for leukemic cells as well as synergy with current therapies.